Process for the manufacture of ether derivatives of 1-benzyl-3-methyl-isoquinoline



UNITED STATES PATENT OFFICE PROCESS FOR THE MANUFACTURE OF ETHER DERIVATIVES OF 1 -BENZYL 3- METHYL-ISOQUINOLINE Otto Wolfes, Darmstadt, Germany No Drawing. Application July 19, 1930, Serial No. 469,262, and in Germany August 24, 1929 9 Claims.

This invention relates to the manufacture of compounds of therapeutic value.

It is known (Bischler 8a Napieralski, Ber. der

deutschen chem.

Gesellschaft 26 (1893) 1903,

Pictet & Finkelstein, Ber. d. deutschen chem. Gesellschaft 42 (1909) 1979) that acid amides which have been phenylacetic acids obtained by'the interaction of and l-phenyl 2 amino ethanes, can often be converted into l-benzyldihydro-isoquinolines under the influence of condensing agents such as zinc chloride, phosphorous pentoxide, phosphorous oxychloride.

That this reaction does not always take place,

but is influenced by certain groups of atoms, is

evident from a work by Callow, Gulland and Haworth (J ourn.

Chemic. Soc. London,-1929, p.

1444). An acetylene derivative having an open chain was obtainedinstead of the expected isoquinoline derivative. Gadamer, Oberlin, Schtiler (Archiv. d. Pharm.

Similarly experiments of 263 (1925) 3 para 2) met-with negative results. It was therefore not to be foreseen whether isoquinoline with an alkyl-group' in position 3 could beprepared according to the above mentioned process.

It has been found by experiment that acid amides which contain-asbasic components, for example, 1 (3,4 methylene dioxyphenyl) -2- amino-propane (German Patent 274,350) are able to close the dihydro-isoquinoline ring under the influence of condensing agents. If in this reaction the acid components are derivatives of phenyl-acetic acid or ethers of oxy derivatives of phenylacetic acid then bases of papaverine-like constitution and physiological action are obtained by dehydrogenation. Some of them are distinguished from papaverine by a more favorable therapeutic index. This was not to be expected because the compounds analogous to papaverine which were already known were not advantageous for medicinal purposes (Mannich 8; Walter, Archiv. d. Phar. 265 (1927) p. 3).

Furthermore it densation takes has been found that the con- 'place at temperatures from 150, the dehydrogenation takes place at 160-220"; more especially the most advantageous temperature for carrying out the condensation is about 105, while is carried out at the dehydrogenation preferably about 180 C. 9 Although any found that phosphorous oxychloride is the .most

suitable condensing agent. The pointed out temperatures of 105 condensing agent and 180 C. and. the mentioned together secure the best yields.

The dehydrogenation may be carried out in an advantageous way only with palladium as catalyst.

As already mentioned the new products are of especial therapeutic value. Particularly 1-(3,4- methylenedioxybenzyl) -3-methy1-6,7-methylene- 60 dioxyisoquinoline has proved to be of high pharmaceutical value. This compound is manufactured as shown in Example 1, shows a melting point of 141, is soluble in chloroform, hot alcohol and hot ether, difficulty soluble in cold alcohol 5 and cold ether, insoluble in water.

It was already known that diand tetrahydropapaverine can be dehydrogenated to papaverine by means of palladium (Spaeth u. Burger, Ber. der deutschen chem. Gesellschaft 60 (192"!) I04), but in this case both the carbon atoms, whose single bond is to be converted into a double bond, carry two hydrogen atoms. In the present case it is a question of dehydrogenation in which one of each of the hydrogen atoms is replaced by an alkyl group whereby the dehydrogenation could be made difiicult and in certain circumstances impossible. As to how little such dehydrogenations were to be foreseen according to literature up to the present, is shown by the 30 work of Shire Akabori and Tazo Suzuki (Proceed. Imp. Acad. Tokyo 5, 255) who were unable to dehydrogenate tetrahydropapaverine as is expressly mentioned by the authors.

Examples (1) 10 parts of the amide (011202) C6H3 CH2CH(CH3) -NH COCH2C6H3(O2 CH2) (prepared from 1-(3',4-methylenedioxyphenyl 2 aminopropane and homopiperonylic acid, melting point -146) are dissolved in 180 parts of hot toluene and heated with 6 parts of phosphorous oxychloride for 3 hours to'about 100 C. The reaction product, which separates out as a dark partly crystalline mass, is separated from the toluene and stirred with parts of water and heated for half an hour, filtered with carbon and allowed to crystallize. The hydrochloride of the new base 100 separates off in prisms which melt at 237 C. with decomposition. The hydrochloride is separated by crystallization and sucking oil. The free base is obtained by adding alkali to the solution of the hydrochloride, taking the reaction product up with ether and evaporating the solution to crystallization. It melts at 103 C. 10 parts of the same are stirred with 1 part of palladium black for 3 hours at about 180 C. The fused mass is dissolved in hot 4 per cent hydrochloric acid, puri- 10 fied with charcoal and allowed to crystallize. The hydrochloride separates off in prisms which contain water of crystallization and melt in an anhydrous state at 254 C. (with decomposition). The free base crystallizes out from methanol in brilliant prisms having a melting point 141 C.

The yield amounts to about 90% of the theoretioal on closing the ring and 75% of theoretical on dehydrogenation. v

The reaction and structural formulas are illus- (2) 10 parts of the amide are dissolved in 150 parts of toluene with heating, and after the addition of a mixture of 10 parts of phosphorous pentoxide in 20 parts of toluene, the

solution is boiled. After cooling the reaction product is stirred, after separation of the toluene, with 100 parts or" water, boiled with charcoal, filtered and the hydrochloride of the new base is separated out by adding common salt.

The temperatures used and other measures are the same as in Example 1.

The free base is, as described in Example 1, dehydrogenated by heating with palladium. The average yield is 60%. The melting point of the new base is 109 C.

The structural formula is as follows;

(3) 150 parts of the amide (CHaO) 2C6H3-CH2-CH(CH3) N'HCOCH2C6H3 (OCHa) 2 (prepared from 1-(3', 4-dimethoxy-phenyl-2- aminopropane and 3, 4 dimethoxyphenyl-acetic acid (homoveratric acid) are dissolved in 1500 parts of hot toluene and heated with 130 parts of phosphorous oxychloride for 6 hours to 100 C. After separating the toluene the reaction product is dissolved in hot water, filtered with charcoal and worked up to the free base by adding am,- monia solution. This base is obtained as a thick oil by taking up in ether, filtering with charcoal and distilling 011 the ether. The methylpapaverine is obtained by heating this oil with one-fourth part of its weight of palladium to about 180. The end product (methyl papaverine) melts, after redissolving fromalcohol, at 136. The hydrochloride crystallizes with water of crystallization. It is obtained in an anhydrous state by crystallizing from alcohol and melts at about 234 with decomposition. The average yield is 60%.

The structural formula of methyl-papaverine is CIIHI (prepared from 1-(3'-4' -dimethoxyphenyl)-2- aminopropane and homopiperonylic acid having a melting point 110) are dissolved in 150 parts of xylene and, after the addition of 10 parts of phosphorous oxychloride, heated to C. The reaction product is worked up to the free base which is dehydrogenated by heating with 10% of palladium black to 190 C. The isoquinolinederivative is repurified from boiling ether. The base melts at 168-169 C. The hydrochloride (crystallized from absolute alcohol) melts at about 233 C. with decomposition. The average yield is 60%;. 125

The structural formula is as follows: 7

CHaO- CHaO N Y.

J)Hz

(5) 10 parts of the amide sition. The average yield is 60%. 50'

(6) 10 parts of the amide (prepared from 1- (3' -4' -methylenedioxyphenyl- 2-aminopropane and ethyl phenylacetic acid,

melting point=l38 are dissolved in 20 parts of hot toluene and heated with 8 parts of phosphorous oxychloride for 3 hours to 105 C. The reaction product is worked up to a free base, which is dehydrogenated with palladium black at about 180 C. and redissolved from alcohol. The substance separates in colorless leaflets which melt at 143. The hydrochloride is very diflicultly soluble in water and melts at about 80 C. Average yield is 70%.

The structural formula is as follows:

/0 CHa H26 I I claim:

1. As a product 1-(3'4'-methylenedioxybenzyl) 3-methyl-6,7-methylenedioxyisoquinoline, a substance soluble in chloroform, hot alcohol and hot ether, difiicultly soluble in cold alcohol and cold ether, insoluble in water, showing a melting point of 141 C., while the hydrochloride of this base melts at 254 C. (under decomposition) the free base showing crystals of brilliant prisms.

2. Process for the production of a 1-benzyl-3- methyl-6,7-dialkoxy-isoquinoline consisting in condensing a phenylacetic acid with 1-(3,4'-dialkoxyphenyl)-2-amino-propane, treating the amide thus obtained with acid condensing agents at a temperature of about 60-150 0.; separating the crystalline hydrochlorides of the bases thus obtained; liberating the free bases from the hydrochlorides by the addition of alkali; and heating the bases with palladium black to about 160- 220 C. for the purpose of dehydrogenation.

3. Process for the production of a 1-(3',4-dialkoxy-benzyl) 3 methyl-6,7 -dialkoxy-isoquinoline consisting in condensing a 3,4-dialkoxyphenylacetic acid with a 1-(3,4'-dialkoxyphenyl)-2-amino-propane, treating the amide thus obtained with acid condensing agents at a temperature of about 60-150 C.; separating the crystalline hydrochlorides of the bases thus obtained; liberating the free bases from the hydrochlorides by the addition of alkali; and heating the bases with palladium black to about 160220 C. for

- V the purpose of dehydrogenation.

' at a temperature of 105 0.; separating the crysmethyl-6,7-dialkoxy-isoquinoline consisting in condensing phenylacetic acid and a 1-(3',4'-dialkoxyphenyl) -2-amino-propane, treating the amide thus obtained with phosphorus oxychloride talline hydrochlorides of the bases thus obtained; liberating the free bases from the hydrochlorides by the addition of alkali; and heating the bases with palladium black to about 180 C. for the purpose of dehydrogenation.

5. Process for the production of a 1-(3,4-dialkoxy-benzyl) -3 methyl-6,7-dihydroxy -isoquinoline consisting in condensing a 3,4-dialkoxyphenylacetic acid with a 1-(3',4-dialkoxyphenyl)-2-amino-propane, treating the amide thus obtainedwith phosphorus oxychloride at a tem-- perature of C., separating the crystalline hydrochlorides of the bases thus obtained; liberating the free bases from the hydrochlorides by the addition of alkali; and heating the bases with palladium black to about 180 C. for the purpose of dehydrogenation.

6. Process for the production of 1-(3',4- methylenedioxybenzyl) -3-methyl-6,7-methylenedioxy-isoquinoline, consisting in condensing homopiperonylic acid and 1-(3,4'-methylenedioxyphenyl) -2-amino-propane, treating the amide thus obtained with acid condensing agents at a temperature of 60150 0., separating the crystalline hydrochloride of the base formed in the preceding step, liberating the free base from the hydrochloride by the addition of alkali; and heating the base thus obtained with finely divided palladium black to 160-220" C. for the purpose of dehydrogenation.

7. Process for the production of 1-(3',4'- methylenedioxybenzyl) -3-methyl-6,7-methylenedioxy-isoquinoline, consisting in condensing homopiperonylic acid and 1-(3',4-methylenedioxyphenyl) -2-amino-propane, treating the amide thus obtained with phosphorus oxychloride at a temperature of 105 C., separating the crystalline hydrochloride of the base formed in the preceding step, liberating the free base from the hydrochloride by the addition of alkali; and heating the base thus obtained with finely divided palladium black to 180 C. for the purpose of dehydrogenation.

8. Process which consists in treating an amide of the type represented by the formula,

wherein each X is hydrogen or alkoxy or both 140,

at a temperature of about 60 C. to 150 C., sepai rating the crystalline hydrochlorides of the bases thus obtained, liberating the free bases from the hydrochlorides by the addition of alkali, and heating the bases with palladium black to about 160220 C; forthe purpose of dehydrogenation,

the product being represented by the general wherein each X is hydrogen or alkoxy or both stand for the methylenedioxy radical, and the Ys represent members of the group consisting of alkoxy and methylenedioxy, and the R stands for hydrogen or alkyl.

9. Process for the production of 1-(3',4'-dia1- koxybenzyl) 3 -methyl- 6,7-dia1koxy -isoquino1ine, consisting in condensing 3,4-dialkoxy-pheny1- acetic acid with 1- (3',4'-dia1koxypheny1) -2- amino-propane, treating the amide thus obtained with acid condensing agents at a temperature of about 60-150 C.; separating the crystalline hydrochloride of the base thus obtained; liberating the free bases from the hydrochlorides by the addition of alkali; and heating the bases with palladium black to about 160-220" C. for the purpose of dehydrogenation. V

OTTO WOLFES. 

